Age-dependent role of type I interferon in Bordetella pertussis pathogenesis

项目概要   最近细菌性疾病百日咳的发病率达到了 60 年来的最高水平。然而， 目前使用的无细胞百日咳疫苗不足，并且没有有效的治疗方法 百日咳。由于抗生素治疗无效，因此需要针对宿主的治疗。然而，我们仍然 对百日咳的发病机制了解甚少，因此尚不清楚其宿主是哪一种 目标适合治疗干预。通过RNAseq转录组学分析，我们发现 I型干扰素（IFN）受体亚基IFNAR1是小鼠最重要的上游激活剂 肺基因因百日咳博德特氏菌感染而差异表达。 I 型干扰素是关键 细胞因子在免疫反应和抗病毒防御中发挥作用，但它们也会加剧炎症和 多种疾病模型中的发病机制。 I 型干扰素对多种细菌具有不同的作用 感染，对某些人有保护作用，对另一些人有害。我们的初步数据表明 I 型干扰素的表达在百日咳博德特氏菌感染的成年小鼠的肺部表达上调，并且它们 加剧肺部炎症病理。然而，在幼年小鼠中，百日咳的发病机制 与成年小鼠（如人类）明显不同，我们的初步数据表明 I 型 IFN 信号传导对百日咳博德特氏菌疾病具有保护作用，表明 I 型 IFN 效应具有年龄依赖性。 我们还一直在研究1-磷酸鞘氨醇（S1P）受体配体作为候选宿主- 百日咳的靶向治疗。 S1P 受体配体药物 FTY720 在人类中用作 治疗复发缓解型多发性硬化症，其他类似药物正在进行各种临床试验 炎症性疾病，证明了这些药物的转化潜力。在已发表的研究中，我们 发现对百日咳博德特氏菌感染的成年小鼠施用单剂量的 S1P 受体配体 显着减少肺部炎症病理。此外，我们的初步数据表明 S1P 受体配体治疗通过下调感染成人的 I 型 IFN 信号传导来减轻炎症 小鼠，与 I 型干扰素加剧肺部炎症病理学的假设一致。 因此，本提案的目的是检验以下假设：(i) I 型干扰素有助于 成年小鼠的肺部炎症病理学和百日咳博德特氏菌病的发病机制，但在小鼠中具有保护作用 幼年小鼠，以及 (ii) S1P 受体药物可减轻百日咳博德特氏菌感染的肺部炎症病理 成年小鼠通过抑制 I 型 IFN 受体信号传导。我们将结合使用小鼠感染和 细胞培养研究来测试这些假设并研究机制，我们将利用 影响 I 型干扰素受体信号传导的基因改造小鼠。宿主目标的识别和 为患有使人衰弱甚至致命的百日咳的患者开发新疗法 将对这种疾病产生重大的公共卫生影响。

PROJECT SUMMARY   Recent levels of the bacterial disease pertussis are at their highest in 60 years. However, the currently used acellular pertussis vaccine is inadequate and no effective therapies exist for treatment of pertussis. Since antibiotic therapy is ineffective, host-targeted therapeutics are needed. However, we still have a very poor understanding of the pathogenesis of pertussis and therefore it is unclear which host targets are appropriate for therapeutic intervention. By RNAseq transcriptomics analysis, we found that the type I interferon (IFN) receptor subunit IFNAR1 was the most significant upstream activator of mouse lung genes differentially expressed in response to Bordetella pertussis infection. Type I IFNs are key cytokines in immune responses and antiviral defense, but they also exacerbate inflammation and pathogenesis in a variety of disease models. Type I IFNs have diverse effects on a variety of bacterial infections, being protective for some and deleterious for others. Our preliminary data indicate that expression of type I IFNs is upregulated in the lungs of B. pertussis-infected adult mice and that they exacerbate lung inflammatory pathology. However, in infant mice, in which the pathogenesis of pertussis is markedly different from that in adult mice (as in humans), our preliminary data suggest that type I IFN signaling is protective against B. pertussis disease, indicating age-dependence of type I IFN effects. We have also been studying sphingosine-1-phosphate (S1P) receptor ligands as candidate host- targeted therapeutics for pertussis. An S1P receptor ligand drug, FTY720, is used in humans as a therapy for relapsing-remitting multiple sclerosis, and other similar drugs are in clinical trials for various inflammatory disorders, demonstrating the translational potential of these drugs. In published studies, we found that administration of a single dose of S1P receptor ligands to B. pertussis-infected adult mice significantly reduced lung inflammatory pathology. Furthermore, our preliminary data suggest that S1P receptor ligand treatment reduces inflammation by downregulating type I IFN signaling in infected adult mice, consistent with the hypothesis that type I IFNs exacerbate lung inflammatory pathology. Therefore, the aims of this proposal are to test the hypotheses that (i) type I IFNs contribute to lung inflammatory pathology and pathogenesis of B. pertussis disease in adult mice but are protective in infant mice, and (ii) S1P receptor drugs attenuate lung inflammatory pathology in B. pertussis-infected adult mice by inhibiting type I IFN receptor signaling. We will use a combination of mouse infection and cell culture studies to test these hypotheses and investigate mechanisms, and we will take advantage of genetically altered mice that impact type I IFN receptor signaling. Identification of host targets and development of novel therapeutics for individuals suffering from debilitating and sometimes fatal pertussis will have a major public health impact on this disease.